In the past few years there has been considerable research effort focused on developing immunotherapeutic regimes for treating cancer. In nearly all of these studies antibodies against tumor-associated antigens have been utilized to treat patients suffering from various malignant disorders, unfortunately, with little success. There appear to be four major reasons for the lack of success, two being: first, tumor-associated antigens are difficult to identify; and, second, it is technically difficult and laborious to prepare homogeneous antibody that recognize tumor-associated antigens. The latter difficulty has been largely circumvented by the development of the hybridoma technique of Kohler and Milstein (Nature, Vol. 256, p.495, 1975), which allows for the unlimited production of monoclonal antibody. As for identifying tumor-associated antigens, there is at present no sure way to identify antigens restricted to cancer cells.
The third problem which must be surmounted when devising an immunotherapeutic regime for treatment of cancer is to prevent an immune reaction against the immunotherapeutic agent, that is, against the antibodies directed to the tumor-associated antigen. This problem is amenable to solution by employing human antibodies generated by modification of the basic Kohler and Milstein technique, as described by Glassy et al in Monoclonal Antibodies and Cancer, eds. Boss et al(1983), Academic Press, and Glassy et al, Proc. Natl. Acad. Sci. USA 80:6327 (1983). Human monoclonal antibodies, when injected into a patient bearing a tumor, recognize and bind to the tumor by binding to the tumor-associated antigen. Since the antibody is of human origin it will not be "seen" as a foreign substance by the patient's immune system and is therefore immunologically blind.
Fourth, most of the human monoclonal antibodies generated to date are of the IgM class. This class of antibody, although useful for a variety of in vitro studies, is not as clinically useful as antibody of the IgG class. The generation of one class of monoclonal antibody over another is, at present, poorly understood, and hence not reproducible.
Despite the advent of methods for generating human-human hydridomas, there have been to date few human hydridomas that secrete monoclonal antibodies against tumor-associated antigens. As described by Handley, Royston and Glassy in Intercellular Communication in Leucocyte Function, Proceedings of the 15th International Leucocyte Culture Conference; Wiley Interscience, N.Y.; p. 617, 1983, human monoclonal antibodies have, however, been generated to date against lung tumors, gliomas, melanomas, and tumors of the prostate and mammary glands. The reason for the paucity of such potentially powerful therapeutic agents is partly due to the technique used to generate the hybridomas. While the general technique is understood conceptually, there are many factors which are poorly understood and yet are responsible for ultimately yielding a human hybridoma cell line. Thus, in essence, there is a great degree of unpredictability in generating human hybridomas that either secrete monoclonal antibody against tumor-associated antigens, or that secrete monoclonal antibody of the preferred IgG class. Indeed there is no assurance prior to attempting to generate a hybridoma that it will, in fact, be obtained at all.
At present immunotherapy has been of little use in treating or diagnosing cancers of the vulva, stomach or other organs for the above mentioned reasons. Thus the establishment of human-human hybrid cell lines that secrete IgG monoclonal antibodies against tumor-associated antigens is sorely needed.